Metastatic Castration Resistant Prostate Cancer
Conditions
Keywords
prostate cancer, advanced prostate cancer, hormone dependent malignancy, hormone resistant, relapsed, refractory, androgen receptor (AR) signaling, metastatic castration resistant prostate cancer (mCRPC), androgen pathway modulator-resistant (APMR), metastatic castration sensitive prostate cancer (mCSPC), androgen pathway modulator-naïve/sensitive (APMN/S), polycomb repressive complex 2 (PRC2)-controlled dysregulation, embryonic ectoderm development (EED), enhancer of zeste homolog 2 (EZH2), ORIC-944, rinzimetostat, mevrometostat, darolutamide, enzalutamide, docetaxel, abiraterone, abiraterone acetate, efficacy, safety, open-label
Brief summary
Himalayas-1 is a randomized, open-label, global, multicenter phase 3 study evaluating whether the combination of rinzimetostat with darolutamide is more effective compared to physician's choice of control; ARPI (darolutamide or enzalutamide) or docetaxel for treating patients with metastatic castration resistant prostate cancer (mCRPC) who were previously treated with abiraterone acetate. The primary objective of this study is to demonstrate superiority in radiographic progression free survival (rPFS) of the investigational arm of rinzimetostat + darolutamide combination versus physician's choice of control: ARPI (darolutamide or enzalutamide) or docetaxel.
Interventions
DRUGRinzimetostat
400 mg once daily (QD)
DRUGDarolutamide
600 mg twice daily (BID)
DRUGEnzalutamide
160 mg once daily (QD)
DRUGDocetaxel
75 mg/m2 intravenously (IV) every 21 days for up to 10 cycles
Sponsors
ORIC Pharmaceuticals
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features * Progressive disease in the setting of surgical or medical castration with evidence of disease progression on treatment with abiraterone acetate in the mCSPC setting or first line mCRPC setting is required * Metastatic disease in bone documented on bone scan, or in soft tissue documented on CT/MRI scan * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Adequate organ function
Exclusion criteria
* Prior treatment for prostate cancer at any stage with cytotoxic chemotherapy, radioligand therapy (ie, 177Lu -PSMA-617, radium-223), ARPIs including apalutamide, darolutamide, and enzalutamide, PARP monotherapy or other systemic anticancer treatment (approved drugs or experimental compounds such as, antibody therapy, immunotherapy, gene or cell therapy, angiogenesis inhibitors, CDK4/6 inhibitors, PRC2 inhibitors) with the following exceptions: 1. Treatment with first-generation antiandrogen agents (eg, bicalutamide, flutamide, nilutamide), but must be discontinued prior to the first dose of study medication 2. Docetaxel treatment is allowed for mCSPC, as long as no signs of failure or disease progression occurred during treatment or within 3 months of treatment completion * Any other anticancer therapy (drug or vaccine which does not meet exclusion criterion 1 above) within 28 days or 5 half-lives (whichever is longer) prior to randomization * Known or suspected brain metastasis or active leptomeningeal disease * Clinically significant cardiovascular disease defined as: * Any medical (including active or clinically significant bacterial, fungal, or viral infection) or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the patient inappropriate for the study * Active inflammatory gastrointestinal disease, chronic diarrhea, or previous gastric resection or lap-band surgery are excluded
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Radiographic Progression Free Survival assessed by blinded independent central review (BICR) per RECIST v1.1 and Prostate Cancer Clinical Trials Working Group 3 (PCWG3) | Randomization up to ~2 years | Radiographic Progression Free Survival is defined as the time from the date of randomization to first evidence of radiographic progression as assessed in soft tissue by RECIST 1.1 or in bone per PCWG3 guideline by BICR, or death, whichever occurs first |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the pharmacokinetics (PK) of rinzimetostat in combination with darolutamide | Randomization up to ~1 year | Rinzimetostat characterized by predose and postdose plasma concentrations at selected time points |
| Overall Survival (OS) | 5 years | OS is defined as time from date of randomization to date of death due to any cause |
| Objective response rate (ORR) | Randomization up to ~2 years | ORR is defined as proportion of patients with measurable soft tissue disease at baseline who have a confirmed objective response of complete response (CR) or partial response (PR) |
| Duration of Response (DoR) | Randomization up to ~2 years | DOR is defined as time of first response to first documentation of radiographic progression or death, whichever occurs first |
| Prostate Specific Antigen (PSA) response | Randomization up to ~2 years | Defined as the proportion of patients with a confirmed ≥50% and ≥90% decline in PSA from baseline as per the PCWG3 criteria, along with the maximum decline in PSA occurring at any point on study |
| Time to PSA progression | Randomization up to ~2 years | Measured from the start of treatment until criteria for PSA progression are met as per PCWG3 |
| Time to initiation of antineoplastic therapy | Randomization up to ~4 years | Time from randomization to first symptomatic skeletal event (symptomatic bone fractures, spinal cord compression, surgery or radiation to the bone whichever is first) |
| Time to first symptomatic skeletal event | Randomization up to ~4 years | Time from randomization to first symptomatic skeletal event (symptomatic bone fractures, spinal cord compression, surgery or radiation to the bone whichever is first) Compare patient reported outcomes (PROs) between the investigational treatment and control arms |
| Change from baseline in patient reported pain symptoms per Brief Pain Inventory-Short Form (BPI-SF) | Randomization up to ~4 years | Analysis of Brief Pain Inventory-Short Form (BPI-SF) will be based on the pain severity score (mean of individual BPI-SF items 3, 4, 5 and 6), the pain interference score (the mean of items 9A-9G), and the single BPI-SF Item 3 which asks the patient to rate pain at its worst in the last 24 hours |
| Change from baseline in health-related quality of life (HRQoL) per Functional Assessment of Cancer Therapy - Prostate (FACT-P) | Randomization up to ~4 years | Change from baseline in HRQoL (FACT-P total score) will be presented. The FACT-P total score will be calculated based on the participant responses to the 39 items in the FACT-P questionnaire. Each item is rated on a 0 to 4 Likert-type scale and then combined to produce the FACT-P total score (0-156), with higher scores representing better health-related quality of life |
| Change from baseline in social/family well-being per Functional Assessment of Cancer Therapy - Prostate (FACT-P) | Randomization up to ~4 years | Change from baseline in social/family well-being score will be presented. The social/family well-being score will be calculated based on 7 items in the FACT-P questionnaire; score range 0-28. Each item is rated on a 0 to 4 Likert-type scale |
| Change from baseline in functioning well-being per Functional Assessment of Cancer Therapy - Prostate (FACT-P) | Randomization up to ~4 years | Change from baseline in functioning well-being score will be presented. The functioning well-being score will be calculated based on 7 items in the FACT-P questionnaire; score range 0-28. Each item is rated on a 0 to 4 Likert-type scale |
| Change from baseline in physical well-being per Functional Assessment of Cancer Therapy - Prostate (FACT-P) | Randomization up to ~4 years | Change from baseline in physical well-being score will be presented. The physical well-being score will be calculated based on 7 items in the FACT-P questionnaire; score range 0-28. Each item is rated on a 0 to 4 Likert-type scale |
| Change from baseline in symptoms per Functional Assessment of Cancer Therapy - Prostate (FACT-P) | Randomization up to ~4 years | Change from baseline prostate cancer symptoms (PCS) score will be presented. The PCS score will be calculated based on 12 items in the FACT-P questionnaire; score range 0-48. Each item is rated on a 0 to 4 Likert-type scale |
| Change from baseline in patient reported health status per European Quality of Life 5-Dimension 5 Level (EQ-5D-5L) | Randomization up to ~4 years | Participants will self-rate their current state of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression by choosing 1 of 5 possible responses that record the level of severity (no problems, slight problems, moderate problems, severe problems, or extreme problems) within each dimension. The questionnaire also includes a visual analog scale to self-rate general health state on a scale from "the worst health you can imagine" to "the best health you can imagine." |
| Symptomatic toxicity as measured by items from the Patient-Reported Outcome CTCAE (PRO-CTCAE) | Randomization up to ~2 years | Each selected PRO-CTCAE items will be assessed related to one or more attributes that include counts for the frequency, severity, and/or interference with usual or daily activities |
| Overall side effect burden as measured by the FACT- GP5 | Randomization up to ~2 years | The FACT-GP5 question assesses overall side effect burden with the following response options "I am bothered by side effects of treatment," is rated on a 5-point scale ranging from "not at all" (0) to "very much" (4) and counts will be presented |
| Time to confirmatory deterioration in patient-reported pain symptoms per BPI-SF Item 3 "worst pain in 24 hours" | Randomization up to ~4 years | Defined as the time from randomization to onset of pain progression, which is defined as \> 2-point increase from baseline in the score from the BPI-SF Question 3 that is confirmed at the next consecutive assessment \> 4 weeks apart or an initial deterioration followed by death before the next assessment |
| Time to definitive deterioration in patient-reported health related quality of life (HRQoL) per FACT-P | Randomization up to ~4 years | Defined as the time from randomization to onset of definitive deterioration in FACT-P total score, which is defined as \>10 point decrease from baseline and no subsequent observations with a \<10 point decrease from baseline FACT-P total score |
| Incidence of Adverse Events (AEs) | Randomization up to ~2 years | Type, incidence, relationship to study treatments, severity, and seriousness of AEs \[as graded by National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) v6.0\] and other clinical assessments |
| Time to definitive deterioration in patient-reported physical well-being per FACT-P | Randomization up to ~4 years | Time to definitive deterioration in physical well-being (PWB) per FACT-P is defined as the time from randomization to onset of definitive deterioration in physical well-being, which is defined as ≥3-point |
Countries
United States
Contacts
CONTACTORIC Clinical Call Center
Outcome results
None listed